The Johns Hopkins HIV Clinical Cohort (JHHCC) has been a resource since 1989 for longitudinal research on the risk factors, treatment and clinical outcomes of persons with HIV (PWH). The Baltimore region has overlapping epidemics of HIV infection and substance use, predominantly heroin and cocaine use, and much of our research has focused in this population, with the advantage of directly comparing those who use substances with a non-use population from the same geographic and socioeconomic catchment areas of the region. Our cohort is predominantly African-American with a high proportion of women, providing a needed window into these epidemics in these often understudied populations. Highly-effective antiretroviral therapy (ART) has markedly improved survival; the median age of the JHHCC cohort is 54 years with an expected life-expectancy of 20-30 years. New federal initiatives have a goal of >90% of PWH in HIV care, so that data to better understand and overcome the challenges to long-term HIV care are particularly relevant to the contemporary epidemic. Our current Aims build upon our strengths in longitudinal research, focusing on the chronically-infected patient population on long- term ART. Non-communicable diseases (NCD) appear to be occurring at higher rates and at earlier ages than expected, even in those who are virally suppressed. We and others have shown that substance use is a barrier to achieving the outcomes of the HIV Care Continuum, and increases the risk of comorbidity and mortality in HIV. Our first Aim is to characterize the extended clinical course of PWH in contemporary HIV care, evaluating the associations of opioid and other substance use and its treatment with the HIV Care Continuum, NCD morbidity and mortality in those aging with HIV. Another focus of the JHHCC has been viral hepatitis co-infection, particularly hepatitis C (HCV), a comorbidity that is prevalent in 40% of our patients, principally because of IDU. Although we are now effectively treating HCV, challenges remain in curing those who use substances and in those who are treated, liver fibrosis is common and the future risk of cirrhosis, steatosis and hepatic cancer is unclear, as well as the risk of re-infection. Our second Aim will focus on HCV treatment and the rates and risks of these adverse liver outcomes and re-infection in those who have been treated. Finally, the JHHCC has a proven history of highly productive collaboration, with over 500 publications, half of which are with multisite collaborations. These include not only observational research, but translational studies of pathogenesis, implementation science and clinical trials. Our third Aim is to enhance collaboration with investigators who would benefit from the resources of the JHHCC, and especially as part of the Collaborating Consortium of Cohorts Producing NIDA Opportunities (C3PNO).